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- Title
Total synthesis of the large non-ribosomal peptide polytheonamide B.
- Authors
Inoue, Masayuki; Shinohara, Naoki; Tanabe, Shintaro; Takahashi, Tomoaki; Okura, Ken; Itoh, Hiroaki; Mizoguchi, Yuki; Iida, Maiko; Lee, Nayoung; Matsuoka, Shigeru
- Abstract
Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 = 68 pg ml−1, mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
- Subjects
NUCLEAR physics; PEPTIDE synthesis; CELL-mediated cytotoxicity; AMINO acids; STEREOCHEMISTRY; CATIONS; PRELEUKEMIA; CHEMICAL structure; REACTIVITY (Chemistry)
- Publication
Nature Chemistry, 2010, Vol 2, Issue 4, p280
- ISSN
1755-4330
- Publication type
Article
- DOI
10.1038/nchem.554